U.S. patent application number 10/976094 was filed with the patent office on 2005-05-26 for dipeptide synthesis.
This patent application is currently assigned to Boehringer Ingelheim Pharmaceuticals, Inc.. Invention is credited to Busacca, Carl Alan, Haddad, Nizar, Kapadia, Suresh R., Lorenz, Jon Charles, Senanayake, Chris Hugh, Smith Keenan, Lana, Wei, Xudong.
Application Number | 20050113572 10/976094 |
Document ID | / |
Family ID | 34572859 |
Filed Date | 2005-05-26 |
United States Patent
Application |
20050113572 |
Kind Code |
A1 |
Busacca, Carl Alan ; et
al. |
May 26, 2005 |
Dipeptide synthesis
Abstract
Disclosed are processes of making dipeptide compounds of
formula(I) as further described in the detailed description
section: 1
Inventors: |
Busacca, Carl Alan;
(Poughkeepsie, NY) ; Haddad, Nizar; (Danbury,
CT) ; Kapadia, Suresh R.; (Danbury, CT) ;
Smith Keenan, Lana; (Poughquag, NY) ; Lorenz, Jon
Charles; (New Milford, CT) ; Senanayake, Chris
Hugh; (Brookfield, CT) ; Wei, Xudong;
(Ridgefield, CT) |
Correspondence
Address: |
MICHAEL P. MORRIS
BOEHRINGER INGELHEIM CORPORATION
900 RIDGEBURY ROAD
P O BOX 368
RIDGEFIELD
CT
06877-0368
US
|
Assignee: |
Boehringer Ingelheim
Pharmaceuticals, Inc.
Ridgefield
CT
|
Family ID: |
34572859 |
Appl. No.: |
10/976094 |
Filed: |
October 27, 2004 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
60515848 |
Oct 30, 2003 |
|
|
|
Current U.S.
Class: |
540/599 ;
540/600; 544/124; 544/238; 544/284; 544/360; 544/60; 546/146;
546/169; 546/207 |
Current CPC
Class: |
C07D 211/66 20130101;
A61P 43/00 20180101 |
Class at
Publication: |
540/599 ;
540/600; 544/360; 544/060; 544/124; 546/207; 544/284; 544/238;
546/146; 546/169 |
International
Class: |
C07D 417/02; C07D
043/02; C07D 413/02 |
Claims
What is claimed is:
1. A process of preparing a compound of the formula (I): 21wherein:
Het is a monocyclic or bicyclic ring which is heterocyclic or a
heteroaryl and contains at least the one nitrogen atom which is
covalently attached to the carbonyl group; Ring a is: azepanyl,
piperidinyl, pyrrolidinyl, azetidinyl, oxepanyl, tetrahydropyranyl,
tetrahydrothiopyranyl, tetrahydrofuranyl, oxetanyl, azocanyl,
oxocanyl, 1,3-diazocanyl, 1,4-diazocanyl, 1,5-diazocanyl,
1,3-dioxocanyl, 1,4-dioxocanyl, 1,5-dioxocanyl, 1,3-oxazocanyl,
1,4-oxazocanyl, 1,5-oxazocanyl, 1,3-diazepanyl, 1,4-diazepanyl,
1,3-dioxepanyl, 1,4-dioxepanyl, 1,3-oxazepanyl, 1,4-oxazepanyl,
1,2-thiazocanyl-1,1-dioxide, 1,2,8-thiadiazocanyl-1,1-dioxide,
1,2-thiazepanyl-1,1-dioxide, 1,2,7-thiadiazepanyl-1,1-dioxide,
tetrahydrothiophenyl, hexahydropyrimidinyl, hexahydropyridazinyl,
piperazinyl, 1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl,
dihydro-oxazolyl, dihydrothiazolyl, dihydroimidazolyl,
isoxazolinyl, oxazolidinyl, 1,2-thiazinanyl-1,1-dioxide,
1,2,6-thiadiazinanyl-1,1-dioxide, isothiazolidinyl-1,1-dioxide,
imidazolidinyl-2,4-dione, imidazolidinyl, morpholinyl, dioxanyl,
tetrahydropyridinyl, thiomorpholinyl, thiazolidinyl,
dihydropyranyl, dithianyl, decahydro-quinolinyl,
decahydro-isoquinolinyl, 1,2,3,4-tetrahydro-quinolinyl, indolinyl,
octahydro-quinolizinyl, dihydro-indolizinyl, octahydro-indolizinyl,
octahydro-indolyl, decahydroquinazolinyl, decahydroquinoxalinyl,
1,2,3,4-tetrahydroquinazolinyl, 1,2,3,4-tetrahydroquinoxalinyl, a
C.sub.6-10 bridged bicyclo wherein one or more carbon atoms are
optionally replaced by a heteroatom chosen from N, O and S, or a
C.sub.4-7 cycloalkyl; each of ring a or Het is optionally
substituted with one or more R.sub.4 which is chosen from hydrogen
and branched or straight chain alkyl, each carbon atom in the alkyl
chain is optionally replaced with one to three heteroatoms chosen
from O, S, and N--R.sub.5 wherein R.sub.5 is hydrogen or alkyl; and
wherein R.sub.5 is optionally further substituted by one or more
alkoxy, amine, halogen, carbocycle, heteroaryl or heterocycle;
R.sub.1 and R.sub.2 are each independently alkyl, alkoxy,
carbocycle, carbocycle(S(O).sub.m--, alkylS(O).sub.m-- wherein m is
0, 1 or 2, heterocycle or heteroaryl; R.sub.3 is cyano, amino or
--C(O)--Ar wherein Ar is a heterocycle, heteroaryl or carbocycle;
said process comprising: a) reacting an allyl alcohol of the
formula (II) with a vinyl ether of the formula (III) in the
presence of a palladium catalyst and a ligand at a temperature
range of 20.degree. C to 120.degree. C., continuing the reaction
for about 7 h at about 100-200.degree. C.; 22where n in formula
(III) is 2, 3, 4 or 5; b) in a one pot reaction, reducing an
intermediate (V) and reacting (V) with a nitrogen containing
heterocycle (VI) where one of the nitrogen atoms bears a reactive
acyl group: --CO--X wherein X is a halogen atom, and subsequently
further reacting with the product (IV) above, to yield as product
intermediate (VII); subsequently reducing (VII) by asymmetric
catalytic hydrogenation to provide ester (VIII); hydrolyzing
intermediate (VIII) to produce the acid (IX): 23c) reacting the
intermediate (IX) produced above with an amine intermediate bearing
ring a under coupling conditions to produce (I): 24and subsequently
isolating the product (I).
2. The process according to claim 1 wherein: Het is chosen from
azepanyl, azocanyl, pyrrolidinyl, piperidinyl, morpholinyl,
thiomorpholinyl, piperazinyl, indolinyl, pyrrolyl, oxazolyl,
isoxazolyl, thiazolyl, imidazolyl, pyridinyl, pyrimidinyl,
pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl, indolyl,
benzimidazolyl, benzthiazolyl, benzisoxazolyl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl, benzoxazinyl
and quinoxalinyl; ring a is piperidinyl, pyrrolidinyl, azetidinyl
or azepanyl; R.sub.1 and R.sub.2 are C.sub.1-5 alkyl; and R.sub.3
is cyano.
3. The process according to claim 2 wherein Het is: 25ring a is
piperidin-4-yl; and R.sub.1 and R.sub.2 are methyl.
4. The process according to any one of claims 1-3 wherein: step a):
the reaction of the allyl alcohol of the formula (II) with a vinyl
ether of the formula (III) in the presence of a palladium catalyst
and a ligand is at a temperature of about 70.degree. C., the
continuing reaction is for about 7 h at about 120-145.degree. C.;
wherein the palladium catalyst is: Pd(OAc).sub.2,
Pd(OCOCF.sub.3).sub.2 or PdCl.sub.2; wherein the ligand is
1,10-phenathroline, 4,7-diphenyl-1,10-phenathroline,
2,2'-dipyridyl; and wherein n in formula (III) is 3; step b): X is
chloro; (VII) is subsequently reduced by asymmetric catalytic
hydrogenation using H.sub.2/Rh--(RRSS)-TangPhos to provide ester
(VIII); (VIII) is subsequently hydrolyzed by a basic hydrolysis
reaction to produce the acid (IX); step c): the coupling conditions
are chosen from 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide
hydrochloride (EDC)/1-hydroxybenzotriazole hydrate (HOBt),
N,N'-Dicyclohexylcarbodiimid- e (DCC), N,N'-diisopropylcarbodiimide
(DIC), O--(1H-Benzotriazol-1-yl)-N,N- ,N'N'-tetramethyl-uronium
hexafluorophosphate, Trimethylacetyl chloride/i-Pr.sub.2NEt,
Trimethylacetyl chloride/Triethylamine, Trimethylacetyl
chloride/N-methylmorpholine, Isobutyl chloroformate/triethylamine,
Isobutyl chloroformate/N-methylmorpholine, Isobutyl
chloroformate/i-Pr.sub.2NEt, Ethylchloroformate/N-methylmorpholi-
ne, 2,4,6-trichlorobenzoly chloride/i-Pr.sub.2NEt,
2,4,6-trichlorobenzoly chloride/triethylamine and
2,4,6-trichlorobenzoly chloride/Nomethylmorpho- line.
5. The reaction according to claim 4 wherein: step a): the
palladium catalyst is Pd(O--C(O)--CH.sub.3).sub.2; the ligand is
1,10-phenathroline; step b): (VIII) is subsequently hydrolyzed by a
basic hydrolysis reaction with aqueous LiOH to produce the acid
(IX); step c): the coupling conditions are EDC and HOBt.
Description
APPLICATION DATA
[0001] This application claims priority to U.S. provisional
application Ser. No. 60/515,848 filed Oct. 30, 2003.
BACKGROUND OF THE INVENTION
[0002] 1. Technical Field
[0003] This invention relates to synthetic processes for preparing
dipeptide compounds possessing pharmacological activity,
particularly as inhibitors of protease enzymes.
[0004] 2. Background Information
[0005] Peptidyl nitrites have been reported as protease inhibitors.
For example, both nitrites and ketoheterocycles are described by B.
A. Rowe et al. (U.S. Pat. No. 5,714,471) as protease inhibitors
useful in the treatment of neurodegenerative diseases. Peptidyl
nitrites are reported by B. Malcolm et al. (WO 9222570) as
inhibitors of picornavirus protease. B. J. Gour-Salin (Can. J.
Chem., 1991, 69, 1288) and T. C. Liang (Arch. Biochim. Biophys.,
1987, 252, 626) described peptidyl nitrites as inhibitors of
papain
[0006] Examples of dipeptide nitrile-based cathepsin S inhibitors
have been reported by Novartis application, WO 99/24460, 1999 and
related U.S. Pat. No. 6,353,017. One of the generic structures is
depicted below. 2
[0007] The processes provided therein provide for converting amides
such as 3
[0008] to the corresponding nitrites and several condensation
reactions of intermediates to arrive at (I). The disadvantages of
these methods are a linear sequence and deprotection/acylation
reations after a chiral center is established which has the
potential problems of racemization
[0009] U.S. Pat. Nos. 6,525,052 and 6,420,364, U.S. provisional
application Ser. No. 60/454,239 each commonly owned by the assignee
of the present application, describe dipeptide nitrites bearing P1
heterocycles. One of the synthetic schemes shown in examples 2,3
and 5 discloses a process beginning with the preparation of
intermediate 2-benzyloxycarbonylamino-5,5-dimethyl-heptanoic acid
for use in the synthesis of particular peptide nitrites disclosed
therein.
[0010] Examples 2, 3 and 5: 45
[0011] Compared to the aforementioned processes, the invention
described herein provides an improved scalable and cost effective
generalized process for preparing dipeptide compounds.
BRIEF SUMMARY OF THE INVENTION
[0012] It is therefore an object of the invention to provide a
process of making dipeptide compounds of formula(I) as further
described in the detailed description section: 6
DETAILED DESCRIPTION OF THE INVENTION
[0013] The present invention has several advantages over similar
known processes. The key intermediate pentene aldehyde (IV) was
synthesis by a novel palladium catalyzed tandem vinyl ether
exchange--Claisen rearrangement process. This process is highly
atomic and volumetric efficient. Known processes are only possible
by using mercury salts as catalyst which is toxic. This process of
the present invention avoided the use of reductant-oxidant found in
the art, therefore it is more environmental friendly and cost
effective.
[0014] Another advantage is that the urea-dehydroamino ester (VII)
was efficiently synthesized by a "one-pot"--3 step sequence. This
avoids isolation/purification work therefore saving solvent and
labor work. The urea-dehydroamino ester (VII) could be purified by
recrystallization which avoided the use of column chromatography
for purification of dehydroamino esters in the art.
[0015] Although asymmetric hydrogenation of dehydroaminoester is
known, the asymmetric hydrogenation of urea-substituted
dehydroamino ester is not known in the art. The present inventors
have successfully developed a highly enantioselective and high
yielding hydrogenation process by using a newly developed catalyst
TangPhos-Rh(COD)OTf.
[0016] In the broadest generic embodiment, there is provided a
method of preparing dipeptide compounds of the formula (I): 7
[0017] wherein:
[0018] Het is a monocyclic or bicyclic ring which is heterocyclic
or a heteroaryl and contains at least the one nitrogen atom which
is covalently attached to the carbonyl group as shown in the
structure.
[0019] Preferred Het include azepanyl, azocanyl, pyrrolidinyl,
piperidinyl, morpholinyl, thiomorpholinyl, piperazinyl, indolinyl,
pyrrolyl, oxazolyl, isoxazolyl, thiazolyl, imidazolyl, pyridinyl,
pyrimidinyl, pyrazinyl, pyridazinyl, tetrazolyl, pyrazolyl,
indolyl, benzimidazolyl, benzthiazolyl, benzisoxazolyl, quinolinyl,
tetrahydroquinolinyl, isoquinolinyl, tetrahydroisoquinolinyl,
quinazolinyl, tetrahydroquinazolinyl, benzoxazolyl, benzoxazinyl
and quinoxalinyl;
[0020] In a most preferred embodiment, Het is: 8
[0021] Ring a is azepanyl, piperidinyl, pyrrolidinyl, azetidinyl,
oxepanyl, tetrahydropyranyl, tetrahydrothiopyranyl,
tetrahydrofuranyl, oxetanyl, azocanyl, oxocanyl, 1,3-diazocanyl,
1,4-diazocanyl, 1,5-diazocanyl, 1,3-dioxocanyl, 1,4-dioxocanyl,
1,5-dioxocanyl, 1,3-oxazocanyl, 1,4-oxazocanyl, 1,5-oxazocanyl,
1,3-diazepanyl, 1,4-diazepanyl, 1,3-dioxepanyl, 1,4-dioxepanyl,
1,3-oxazepanyl, 1,4-oxazepanyl, 1,2-thiazocanyl-1,1-dioxide,
1,2,8-thiadiazocanyl-1,1-dio- xide, 1,2-thiazepanyl-1,1-dioxide,
1,2,7-thiadiazepanyl-1,1-dioxide, tetrahydrothiophenyl,
hexahydropyrimidinyl, hexahydropyridazinyl, piperazinyl,
1,4,5,6-tetrahydropyrimidinyl, pyrazolidinyl, dihydro-oxazolyl,
dihydrothiazolyl, dihydroimidazolyl, isoxazolinyl, oxazolidinyl,
1,2-thiazinanyl-1,1-dioxide, 1 ,2,6-thiadiazinanyl-1,1-diox- ide,
isothiazolidinyl-1,1-dioxide, imidazolidinyl-2,4-dione,
imidazolidinyl, morpholinyl, dioxanyl, tetrahydropyridinyl,
thiomorpholinyl, thiazolidinyl, dihydropyranyl, dithianyl,
decahydro-quinolinyl, decahydro-isoquinolinyl,
1,2,3,4-tetrahydro-quinoli- nyl, indolinyl, octahydro-quinolizinyl,
dihydro-indolizinyl, octahydro-indolizinyl, octahydro-indolyl,
decahydroquinazolinyl, decahydroquinoxalinyl,
1,2,3,4-tetrahydroquinazolinyl or
1,2,3,4-tetrahydroquinoxalinyl;
[0022] a C.sub.6-10 bridged bicyclo wherein one or more carbon
atoms are optionally replaced by a heteroatom chosen from N, O and
S;
[0023] or
[0024] a C.sub.4-7 cycloalkyl.
[0025] Preferred ring a include piperidinyl, pyrrolidinyl,
azetidinyl and azepanyl; most preferred is piperidin-4-yl.
[0026] Each of ring a or Het is optionally substituted with one or
more R.sub.4 which is chosen from hydrogen or alkyl branched or
straight chain alkyl, each carbon atom in the chain is optionally
replaced with one to three heteroatoms chosen from O, S, and
N--R.sub.5 wherein R.sub.5 is hydrogen or alkyl; and wherein
R.sub.5 is optionally further substituted by one or more alkoxy,
amine, halogen, carbocycle, heteroaryl or heterocycle;
[0027] R.sub.1 and R.sub.2 are each independently alkyl, alkoxy,
carbocycle, carbocycle(S(O).sub.m--, alkylS(O).sub.m-- wherein m is
0, 1 or 2, heterocycle or heteroaryl. Preferred R.sub.1 and R.sub.2
is C.sub.1-5 alkyl, most preferred is methyl.
[0028] R.sub.3 is cyano, amino or --C(O)--Ar wherein Ar is a
heterocycle, heteroaryl or carbocycle, preferably R.sub.3 is
cyano;
[0029] said process comprising:
[0030] a) reacting an allyl alcohol of the formula (II) with a
vinyl ether of the formula (III) in the presence of a palladium
catalyst and a ligand at a temperature range of 20.degree. C. to
120.degree. C., preferably about 70.degree. C. A novel feature in
this reaction step is that a vinyl ether exchange is combined with
a Claisen rearrangement, the reaction occurs for about 7 h at about
100-200.degree. C., preferably 120-145.degree. C. Palladium
catalysts include: Pd(OAc).sub.2, Pd(OCOCF.sub.3).sub.2,
PdCl.sub.2, a preferred catalyst is Pd(O--C(O)--CH.sub.3).sub.2;
Ligands include: 1,10-phenathroline,
4,7-diphenyl-1,10-phenathroline, 2,2'-dipyridyl. A preferred ligand
is 1,10-phenathroline. 9
[0031] where n in formula (III) is 2, 3, 4 or 5 preferably 3.
[0032] b) In a one pot reaction, intermediate (V) is reduced and
reacted with a nitrogen containing heterocycle (VI) where one of
the nitrogen atoms bears an reactive acyl group such as --CO--X
wherein X is a halogen atom, preferably chloro, and subsequently
further reacted with the product (IV) above, to yield as product
the novel intermediate (VII); (VII) is subsequently reduced by
asymmetric catalytic hydrogenation such as
H.sub.2/Rh--(RRSS)--TangPhos under suitable conditions to provide
ester (VIII). Intermediate (VIII) is subsequently hydrolyzed,
preferably by a basic hydrolysis reaction, more preferably with
aqueous LiOH to produce the acid (IX): 10
[0033] c) The intermediate (IX) produced above is subsequently
reacted with an amine intermediate bearing ring a under suitable
coupling conditions such as EDC/HOBt, N,N'-Dicyclohexylcarbodiimide
(DCC), N,N'-diisopropylcarbodiimide (DIC),
O-(1H-Benzotriazol-1-yl)-N,N,N'N'-tet- ramethyl-uronium
hexafluorophosphate, Trimethylacetyl chloride/i-Pr.sub.2NEt,
Trimethylacetyl chloride/Triethylamine, Trimethylacetyl
chloride/N-methylmorpholine, Isobutyl chloroformate/triethylamine,
Isobutyl chloroformate/N-methylmorpholine, Isobutyl
chloroformate/i-Pr.sub.2NEt, Ethylchloroformate/N-methylmorpholi-
ne, 2,4,6-trichlorobenzoly chloride/i-Pr.sub.2NEt,
2,4,6-trichlorobenzoly chloride/triethylamine,
2,4,6-trichlorobenzoly chloride/Nomethylmorpholin- e, preferably
using 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride
(EDC) and 1-hydroxybenzotriazole hydrate (HOBt) to produce (I):
11
[0034] Unless otherwise noted, any compounds produced by the
methods of this invention which contain one or more asymmetric
carbon atoms may occur as racemates and racemic mixtures, single
enantiomers, diastereomeric mixtures and individual diastereomers.
All such isomeric forms of these compounds are expressly included
in the present invention. Each stereogenic carbon may be in the R
or S configuration unless otherwise specified, or a combination of
configurations.
[0035] In preferred embodiments of the invention, in product
compounds the P2 chiral carbon is the (S) enantiomer which
possesses a natural amino acid configuration.
[0036] Some of the compounds of the invention can exist in more
than one tautomeric form. The invention includes producing all such
tautomers.
[0037] It shall be understood by one of ordinary skill in the art
that all compounds produced by the methods disclosed herein are
those which are chemically stable.
[0038] In order that the invention herein described may be more
fully understood, the following detailed description is set forth.
As used herein, the following abbreviations are used:
[0039] BOC or t-BOC is tertiary-butoxycarbonyl;
[0040] t-Bu is tertiary-butyl;
[0041] DMF is dimethylformamide;
[0042] EtOAc is ethyl acetate;
[0043] OAc is acetate;
[0044] THF is tetrahydrofuran;
[0045] NMM is 4-methyl morpholine
[0046] CH.sub.2Cl.sub.2 is dichloromethane;
[0047] MgSO.sub.4 is magnesium sulfate;
[0048] Na.sub.2SO.sub.4 is sodium sulfate;
[0049] Ar is argon;
[0050] EDC is 1-(3-dimethylaminopropyl)-3-ethylcarbodimide
hydrochloride and
[0051] HOBT is 1-hydroxybenzotriazole;
[0052] DBU is 1,8-diazabicyclo[5.4.0]undec-7-ene;
[0053] MTBE is tert-butyl methyl ether.
[0054] Also, as used herein, each of the following terms, used
alone or in conjunction with other terms, are defined as follows
(except where noted to the contrary):
[0055] The term "alkyl" refers to a saturated aliphatic radical
containing from one to ten carbon atoms or a mono- or
polyunsaturated aliphatic hydrocarbon radical containing from two
to twelve carbon atoms. The mono- or polyunsaturated aliphatic
hydrocarbon radical containing at least one double or triple bond,
respectively. "Alkyl" refers to both branched and unbranched alkyl
groups. Examples of "alkyl" include alkyl groups which are straight
chain alkyl groups containing from one to eight carbon atoms and
branched alkyl groups containing from three to eight carbon atoms.
Other examples include lower alkyl groups which are straight chain
alkyl groups containing from one to six carbon atoms and branched
alkyl groups containing from three to six carbon atoms. It should
be understood that any combination term using an "alk" or "alkyl"
prefix refers to analogs according to the above definition of
"alkyl". For example, terms such as "alkoxy", "alkythio" refer to
alkyl groups linked to a second group via an oxygen or sulfur atom.
"Alkanoyl" refers to an alkyl group linked to a carbonyl group
(C.dbd.O). Each alkyl or alkyl analog described herein shall be
understood to be optionally partially or fully halogenated.
[0056] Carbocycle refers to "aryl" being aromatic ot partially
saturated, or a nonaromatic cycloalkyl.
[0057] The term "cycloalkyl" refers to the cyclic analog of an
alkyl group, as defined above. Examples of cycloalkyl groups are
saturated or unsaturated nonaromatic cycloalkyl groups containing
from three to eight carbon atoms, and other examples include
cycloalkyl groups having three to six carbon atoms. Each cycloalkyl
described herein shall be understood to be optionally partially or
fully halogenated.
[0058] The term "aryl" refers to phenyl and naphthyl.
[0059] The term "halogen" refers to a halogen radical selected from
fluoro, chloro, bromo or iodo.
[0060] The term "heteroaryl" refers to a stable 5-8 membered (but
preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic
aromatic heterocycle radical. Each heterocycle consists of carbon
atoms and from 1 to 4 heteroatoms chosen from nitrogen, oxygen and
sulfur. The heterocycle may be attached by any atom of the cycle,
which results in the creation of a stable structure. Unless
otherwise defined, examples of "heteroaryl" include radicals such
as furanyl, thienyl, pyrrolyl, oxazolyl, thiazolyl, imidazolyl,
pyrazolyl, isoxazolyl, isothiazolyl, oxadiazolyl, triazolyl,
tetrazolyl, thiadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, indolizinyl, indolyl, isoindolyl, benzofuranyl,
benzothienyl, indazolyl, benzimidazolyl, benzthiazolyl,
benzoxazolyl, purinyl, quinolizinyl, quinolinyl, isoquinolinyl,
cinnolinyl, phthalazinyl, quinazolinyl, quinoxalinyl,
naphthyridinyl, pteridinyl, carbazolyl, acridinyl, phenazinyl,
phenothiazinyl and phenoxazinyl,
[0061] The term "heterocycle" refers to a stable 4-8 membered (but
preferably, 5 or 6 membered) monocyclic or 8-11 membered bicyclic
heterocycle radical which may be either saturated or unsaturated,
and is non-aromatic. Each heterocycle consists of carbon atoms and
from 1 to 4 heteroatoms chosen from nitrogen, oxygen and sulfur.
The heterocycle may be attached by any atom of the cycle, which
results in the creation of a stable structure. Unless otherwise
defined, examples of "heterocycle" include radicals such as
pyrrolinyl, pyrrolidinyl, pyrazolinyl, pyrazolidinyl, piperidinyl,
morpholinyl, thiomorpholinyl, pyranyl, thiopyranyl, piperazinyl,
indolinyl, azetidinyl, tetrahydropyranyl, tetrahydrothiopyranyl,
tetrahydrofuranyl, hexahydropyrimidinyl, hexahydropyridazinyl,
1,4,5,6-tetrahydropyrimidin-2-ylamine, dihydro-oxazolyl,
1,2-thiazinanyl-1,1-dioxide, 1 ,2,6-thiadiazinanyl-1,1-- dioxide,
isothiazolidinyl-1,1-dioxide and imidazolidinyl-2,4-dione.
[0062] The terms "heterocycle", "heteroaryl" or "aryl", when
associated with another moiety, unless otherwise specified shall
have the same meaning as given above. For example, "aroyl" refers
to phenyl or naphthyl linked to a carbonyl group (C.dbd.O).
[0063] Each aryl or heteroaryl unless otherwise specified includes
it's partially or fully hydrogenated derivative. For example,
quinolinyl may include decahydroquinolinyl and
tetrahydroquinolinyl, naphthyl may include it's hydrogenated
derivatives such as tetrahydranaphthyl. Other partially or fully
hydrogenated derivatives of the aryl and heteroaryl compounds
described herein will be apparent to one of ordinary skill in the
art.
[0064] The term "amine" shall be understood to mean an --NH.sub.2
group wherein each hydrogen atom may be replaced by alkyl,
carbocycle, carbocyclealkyl, heteroaryl, heteroarylalkyl,
heterocycle, heterocyclealkyl such that the amine nitrogen may be
mono- or di-substituted by said groups.
[0065] As used herein above and throughout this application,
"nitrogen" and "sulfur" include any oxidized form of nitrogen and
sulfur and the quaternized form of any basic nitrogen.
[0066] In order that this invention be more fully understood, the
following examples are set forth. These examples are for the
purpose of illustrating preferred embodiments of this invention,
and are not to be construed as limiting the scope of the invention
in any way.
[0067] The examples which follow are illustrative and, as
recognized by one skilled in the art, particular reagents or
conditions could be modified as needed for individual compounds.
Starting materials used in the scheme below are either commercially
available or easily prepared from commercially available materials
by those skilled in the art. Further reference in this regard may
be made to U.S. Pat. Nos. 6,525,052 and 6,420,364, U.S. provisional
application Ser. No. 60/454,239.
[0068] All journal and patent references cited in this application
are incorporated herein by reference in their entirety.
EXAMPLES
Synthesis of 3,3-Dimethylpent-4-enal by Sequential Vinylether
Formation and Claisen Rearrangement
[0069]
1 12 13 14 Compound MW Mass Mol eq 3-methyl-2-butenol 86 1.72 Kg 20
mol 1.0 Triethyleneglycol divinyl ether 202 6.06 Kg 30 mol 1.5
Pd(OAc).sub.2 224 22.4 g 0.1 mol 0.005 1,10-phenathroline 180 18.0
g 0.1 mol 0.005 1,4-Butynediol 43 12.0 g 0.28 mol 0.014
[0070] Pd(OAc).sub.2 (22.4 g, 0.1 mol) and 1,10-phenathroline (18.0
g, 0.1 mol) were added to a 12 L 3-neck flask. Triethyleneglycol
divinyl ether (6.06 kg, 6 L, 30 mol) was added, and the mixture was
stirred at room temperature for 20 minutes while a lemon yellow
suspension was formed. 3-Methyl-2-butenol (1.72 kg, 2 L, 20 mol)
was added, and the reaction mixture was heated gently to
68-70.degree. C. The reaction became a clear yellow solution at
this point. After stirring for 5-7 h, NMR showed that about 80% of
3-methyl-2-butenol had been converted to its vinyl ether.
1,4-Butynediol (12 g, 0.28 mol) was added, and the reaction mixture
was then heated up to 110-120.degree. C. The temperature was raised
gradually to 145.degree. C. within ca. 1 h in order to maintain the
reflux and then kept at this temperature for 5-10 h until
.sup.1H-NMR showed the rearrangement finished. The reaction mixture
was cooled to ca. 120.degree. C. and distilled under vacuum. The
fraction at ca. 90.degree. C./300 mm Hg was collected. 1.34 kg of
the desired product was obtained (60% yield) as colorless
liquid.
[0071] "One pot" Synthesis of Dehydrourea Ester (Steps 2-4): 15
Hydrogenation of N-(benzyloxy carbonyl)-.alpha.-phosphonoglycine
trimethyl ester
[0072] A dry 20 L autoclave was pressure tested at 100 psi with
N.sub.2 then vented, and placed under vacuum. A solution of
Cbz-.alpha.-phosphono glycine trimethylester (3.0 kg 9.06 mol) in
THF (12 L) was transferred into the autoclave using residual
vacuum. The cooling water for the agitator was turned on, the batch
was agitated at 500 to 700 rpm, and the autoclave was purged with
N.sub.2 for 10-15 min, then placed under a slight vacuum. A slurry
of Degussa type E101 NE/W .about.50% H.sub.2O wet Pd/C (600 g, 10
wt %) in a minimal amount of THF was transferred to the reactor
using residual vacuum. The reactor was sealed, purged with
nitrogen, pressurized to 10 psi with hydrogen and vented twice. The
reactor was filled to 100 psi using a line with a check valve, and
the line was left open to maintain the internal pressure at 100
psi. After 4 h the H.sub.2 was slowly vented, a sample was taken
for HPLC to confirm the reaction contained less than 2% starting
material. Using vacuum the reaction was transferred to a filter
funnel containing MgSO.sub.4 (1 kg) to remove the Pd/C and
H.sub.2O. The pad was rinsed with THF and the filtrated taken
directly to the next step.
[0073] Note: Do not allow the pad to become dry during the
filtration, fire hazard.
[0074] Note: The amino phosphono ester generated in this reaction
is extremely unstable when concentrated and can decompose
explosively.
[0075] Urea Formation
[0076] The above amine-containing solution was transferred to a 50
L flask fitted with a mechanical stirrer, thermocouple and nitrogen
inlet. The 4-morpholine carbonyl chloride (1.25 L, 10.9 mol) and
N-methyl morpholine (1.64 L, 14.9 mol) were added at 17.degree. C.,
there was a mild delayed exotherm of a few degrees, and the
reaction was left overnight. The reaction was followed by .sup.31P
NMR, or LCMS. When the reaction was complete it was used without
work-up or purification in the next step.
[0077] Horner Emmons Wadsworth Reaction
[0078] The slurry of urea phosphono ester in THF was cooled to
about 10.degree. C. and 3,3-dimethyl-4-pentenal (1.35 kg, 83% pure,
1.0 mol) was added, with a THF rinse (2 L). The DBU (2.9 kg, 19
mol) was charged to an addition funnel and added to the reaction
dropwise over 3.5 h while maintaining the internal temperature of
the reaction between 6-17.degree. C. After the addition was
complete the reaction was allowed to slowly warm to room
temperature and followed by LCMS. When the phosphonate had been
consumed by LCMS the slurry was cooled in an ice bath to about
4.degree. C. and 4 M HCl (12 L) was slowly dripped into the
reaction over 2.5-3.5 h, while keeping the reaction temperature
below 20.degree. C. The layers were then separated, the aqueous
layer was extracted with EtOAc (2.times.8 L), the organic layers
were combined, washed with 1 M HCl (6 L) and concentrated by
distillation to give the crude product as a slurry/solid.
[0079] Crystallization
[0080] The two batches were combined, EtOAc (4 L) was added, then
distilled off under hose vacuum below 50.degree. C. to remove most
of the THF. The crude material was mixed with EtOAc (1.8 L) and
heptane (3.8 L) and heated in a water bath to 70.degree. C., a
solution formed at about 66.degree. C. The solution's temperature
was slowly lowered to ambient over several h then left to stir at
ambient temperature overnight. The solid was collected by vacuum
filtration, and the flask was rinsed with the mother liquors. The
off white solid was dried in a vacuum oven below 40.degree. C. with
a nitrogen purge to yield 3.7 kg with an E/Z ration of 1/126.
[0081] The product was further purified by slurrying the dehydro
urea ester (3.6 kg) in a 22 L flask with H.sub.2O (9 L) for 2.5 h,
collecting the white solid by vacuum filtration, and drying in a
vacuum oven below 40.degree. C. to give 2.98 kg of the desired
product as a fluffy white solid.
Synthesis of Substituted Chiral Amino Ester by Asymmetric
Hydrogenation
[0082]
2 16 17 Compound MW Mass Mol eq Dehydro amino ester 296 1.5 kg 5.0
mol 1 Rh(COD).sub.2OTf 468 2.34 g 0.005 mol 0.001 (RRSS)-TangPhos
286 1.57 g 0.0055 mol 0.0011 MeOH 6 L solvent Pd-C (10%, 50% wet)
75 g (1:20)
[0083] Preparation of Chiral Catalyst:
[0084] Rh(COD).sub.2OTf and ligand were mixed in methanol (500 ml)
under Ar. The solution was stirred at ambient temperature for 30
min. Hydrogen was bubbled through it for another 15 min.
[0085] Asymmetric Hydrogenation:
[0086] The dehydroaminoester in 5.5 L methanol was added to an
autoclave. The solution was purged with hydrogen at 30 psi 4 times.
The solution of chiral catalyst was added with a canula, and the
reaction mixture was stirred under 50 psi hydrogen for 10 h at
ambient temperature. NMR and HPLC both indicated the disappearance
of starting material.
[0087] Hydrogenation of Terminal Alkene (Pd--C):
[0088] Hydrogen pressure was released. To the reaction mixture was
added palladium on charcoal (75 g), and the reaction mixture was
purged with hydrogen (30 psi) 3 times. The reaction mixture was
stirred under 50 psi hydrogen for 3 h. NMR and HPLC indicated the
completion of reaction. Pd--C was removed by filtration through a
diatomaceous earth pad. The solution was used in the next step
directly without further purification. HPLC assay showed 1.5 kg of
product was obtained, yield >99%, ee 99% based on chiral
HPLC.
[0089] Hydrolysis of Chiral Amino Ester to Acid: 18
[0090] To a 22 L three neck flask fitted with a mechanical stirrer
and nitrogen inlet was added the ester (1.40 kg, 4.66 mole).
Methanol (4.20 L) and THF (4.20 L) were charged into the flask and
the contents were stirred until a clear solution was obtained. A
solution of lithium hydroxide (215.10 g, 5.13 mole, 1.1 eq) in 4.20
L of water was added slowly to the flask. The reaction temperature
was maintained below 30.degree. C. using a cold water bath. At the
end of the addition the cold bath was removed and the reaction
mixture was stirred at 22.+-.2.degree. C. for 2 h. The pH of the
reaction mixture was adjusted to about 5-6 by the addition of 2N
HCl (1.40 L) keeping the internal temperature between 15-20.degree.
C. The mixture was subjected to distillation under reduced pressure
to remove volatile solvents (MeOH and THF). The residue was
adjusted to pH .about.3 with 2N HCl (1.82 L) and extracted with
MTBE (2.times.4.66 L). The combined organic phase was washed with
saturated brine (2.30 L). The organic layer containing the acid
(about 11.8 L) was concentrated by distillation of MTBE to a
minimum stirrable volume. MTBE (9.30 L) was added and the resulting
mixture distilled under reduced pressure. Anhydrous THF (9.30 L)
was then added to the residue and distilled under reduced pressure
to a minimum stirrable volume. Anhydrous THF (7.0 L) was added to
the residue. The solution was assayed by HPLC and stored it in a
cool dry place under nitrogen.
[0091] Procedure for Amide Coupling:
3 19 20 Material MW eq. Mol Amount Acid (ee = 99.4%) 286.37 1 4.19
1.20 Kg HOBT.H.sub.2O 153.14 1.32 5.53 0.847 Kg EDC 191.7 1.37 5.76
1.105 Kg Aminonitrile 139.2 1.15 4.82 0.671 Kg THF 2.88 L DMF 2.88
L
[0092] To a solution of acid (1.20 kg, 4.19 mol) in THF (2.8 L) was
added anhydrous DMF (2.88 L) and HOBT (0.706 kg, 4.61 mol). EDC
(0.884 kg, 4.61 mol) was added in several portions keeping
temperature between 15 and 17.degree. C. After stirring for 1 h,
the aminonitrile (0.671 kg, 4.82 mol) was added over 45 min
(T<20.degree. C.) and the reaction mixture was stirred for 3 h.
At this time remaining HOBT (0.141 kg) and EDC (0.221 kg) were
added and stirred for 16 h at ambient temperature. The reaction
mixture was filtered to remove particulate matter and quenched by
pouring into 7% sodium bicarbonate solution (29 L). The mixture was
stirred for 4 h at ambient temperature. The product was filtered
and washed with water (3.times.5 L) and dried under N.sub.2.
Isolated yield: 1.32 kg (77.3%), ee=100%, purity 97.55% by
HPLC.
* * * * *